US4699899A - Substituted O-sulphonyl-glycosylamides, processes for their preparation and their use as medicaments - Google Patents
Substituted O-sulphonyl-glycosylamides, processes for their preparation and their use as medicaments Download PDFInfo
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- US4699899A US4699899A US06/832,482 US83248286A US4699899A US 4699899 A US4699899 A US 4699899A US 83248286 A US83248286 A US 83248286A US 4699899 A US4699899 A US 4699899A
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000012419 Thalia geniculata Nutrition 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- UEPBUDKELPZGFG-UYBIQSCLSA-N [(2r,3s,4s,5r,6r)-6-[dodecanoyl(octadecyl)amino]-3,4,5-trihydroxyoxan-2-yl]methyl methanesulfonate Chemical compound CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H]1O UEPBUDKELPZGFG-UYBIQSCLSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
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- 230000007503 antigenic stimulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 125000002511 behenyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 230000003115 biocidal effect Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical compound NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 description 1
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- 150000001723 carbon free-radicals Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- HDFRDWFLWVCOGP-UHFFFAOYSA-N carbonothioic O,S-acid Chemical class OC(S)=O HDFRDWFLWVCOGP-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- AZZCHVHSWUYCQA-UHFFFAOYSA-N decyl carbonochloridate Chemical compound CCCCCCCCCCOC(Cl)=O AZZCHVHSWUYCQA-UHFFFAOYSA-N 0.000 description 1
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- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 1
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- 238000013401 experimental design Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- 238000002649 immunization Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000002434 immunopotentiative effect Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000002463 lignoceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000243 mutagenic effect Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 125000001802 myricyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WFMKUKPIVUIKTE-SCSBQZQXSA-N n-dodecyl-n-[(3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O WFMKUKPIVUIKTE-SCSBQZQXSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000015323 positive regulation of phagocytosis Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical class OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003558 thiocarbamic acid derivatives Chemical class 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
Definitions
- the invention relates to compounds of the general formula I ##STR5## in which X represents hydrogen or the radical --CH 2 OR 5 ,
- Z represents OR 4 or NHV
- V denotes hydrogen or ##STR6##
- Y and W are identical or different and represent oxygen, sulphur, N--H or CH 2 ,
- R 2 , R 3 , R 4 and R 5 are identical or different and represent hydrogen or the radical ##STR7## with the proviso that at least one of the radicals R 2 , R 3 , R 4 and R 5 denotes ##STR8## and R 1 , R 6 , R 7 and R 8 are identical or different and represent an optionally substituted hydrocarbon radical with up to 50 carbon atoms,
- a carbon radical in the meaning of radicals R 1 , R 6 , R 7 and R 8 is undestood, according to the invention, as meaning a straight-chain or branched alkyl radical, a straight-chain or branched, mono- or polysubstituted unsaturated alkenyl radical, a saturated or unsaturated alicyclic radical or an aromatic radical (aryl).
- aryl aromatic radical
- R 1 , R 6 , R 7 and R 8 that is to say, for example, as alkylcycloalkyl, arylalkyl, alkylaryl, alkenylcycloalkyl and the like.
- hydrocarbon radicals R 1 , R 6 , R 7 and R 8 individual, in general up to 5, preferably 1, 2 or 3, methylene or methine groups can also be replaced by O, S and/or N. If the chain is interrupted by N, this nitrogen carries either H or a C 1 -C 20 --alkyl radical or a --CO--alkyl radical, this alkyl group containing 1-20 C atoms.
- R 6 preferably represents an alkyl radical with 1 to 21 C atoms, preferably with 1-4 C atoms, or represents an optionally substituted aryl radical with up to 21 C atoms, preferably with up to 7 C atoms.
- saturated radicals which may be mentioned here are methyl, ethyl, propyl, i-propyl, butyl and i-butyl.
- aryl are halogen-substituted, preferably chlorine- or bromine-substituted, or nitro-, cyano-, amido--C 1 -C 4 --alkyl- or C 1 -C 4 --alkoxy-substituted phenyl, naphthyl or biphenyl.
- R 1 , R 7 and R 8 represent, as desired, alkyl or alkenyl radicals with 1 to 21 carbon atoms, preferably with 9 to 21 C atoms.
- saturated radicals which may be mentioned here are methyl, ethyl, propyl, i-propyl, butyl, i-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, docosyl, ethylpentyl, methyldecyl, i
- Unsaturated radicals are, for example, vinyl, 1-propenyl, 2-propenyl, i-butenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-decenyl, 5-decenyl, 9-decenyl, 8-heptadecenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-pentadienyl, 8,11-heptadecanedienyl and 8,11,14-heptadecanetrienyl.
- the longer-chain unsaturated radicals are preferred, especially the mono- or diunsaturated alkenyls with 9-21 C atoms.
- the unsaturated hydrocarbon radicals can thereby be present as pure cis- or trans-isomers or as isomer mixtures.
- cycloalkyl examples include cyclopentyl, cyclohexyl, decahydronaphthyl and adamantyl.
- alkyl-cycloalkyl and cycloalkyl-alkyl radicals are methylcyclopentyl, ethylcyclopentyl, n-propylcyclopentyl, i-propylcyclopentyl, butylcyclopentyl, octylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, propylcyclohexyl, butylcyclohexyl, hexylcyclohexyl, decylcyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclopentylhexyl, cyclopentyloctyl, cyclopentyldecyl, cyclohexylmethyl, cyclohexylethyl,
- aryl examples include phenyl, tosyl, naphthyl and diphenyl.
- aralkyl examples include aryl-lower alkyl, such as benzyl, phenethyl or phenylhexyl.
- R 1 , R 6 , R 7 and R 8 can be substituted, in general 1-5 times, preferably 1-3 times.
- Preferred possible substituents are the following: halogen, preferably F, Cl or Br, amino, C 1 -C 6 --alkylamino, di--C 1 -C 6 --alkylamino, oxo, OH, C 1 -C 6 --alkoxy, SH, C 1 -C 6 --alkylthio, C 1 -C 6 --alkyl--COO and C 1 -C 6 --alkyl--CO--NH.
- Examples of cases in which the hydrocarbon radicals R 1 , R 7 and R 8 are interrupted by O, S and N or corresponding atom groupings, or are substituted, for examples, by groups containing these atoms or by halogen atoms, are methoxyethyl, ethoxyethyl, n-propoxyethyl, n-butoxyethyl, i-propoxyethyl, i-butoxyethyl, sec.-butoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, propoxyethoxyethyl, i-propoxyethoxyethyl, n-butoxyethoxyethyl, i-butoxyethoxyethyl, sec.-butoxyethoxyethyl, methoxyethoxyethoxyethyl, ethoxyethoxyethoxyethyl, n-propoxyethoxyethoxy
- the compounds of the formula I contain several chiral C atoms and are present as optical pure diastereomers or as diastereomer mixtures.
- the compounds of the formula I according to the invention are thus carboxylic acid amides or N-alkylated or N-aralkylated carboxylic acid amides or carbamic acid, thiocarbamic acid or urea derivatives which additionally carry on the nitrogen atom substituted by the abovementioned radical R 7 a single monosaccharide radical which is N-glycosidically bonded, that is to say via the anomeric carbon atom, one or more hydroxyl groups in the saccharide radical being provided with a sulphonyl radical.
- Particularly preferred compounds are those in which only one of the radicals R 2 , R 3 , R 4 or R 5 denotes SO 2 -R 6 , with the proviso that the other radicals R 2 , R 3 , R 4 and/or R 5 represent hydrogen and R 6 and Z have the abovementioned meaning.
- R 2 , R 3 and R 4 represent hydrogen and R 5 represents the radical SO 2 --R 6 , Z and R 6 having the abovementioned meaning.
- the invention also relates to processes for the preparation of the compounds of the formula I.
- Z' represents OH or NHCO--W--R 8 ,
- R 8 and W have the abovementioned meaning, are first reacted, either in the free, that is to say unprotected, form or in the form of protected, optionally activated derivatives, with an amino compound R 7 --NH 2 , either in the free form or in the form of a suitable acid addition salt with the meaning of R 7 described above, and the glycosylamine thereby obtained is then acylated with an activated--as is customary in acylation reactions--carboxylic acid, carbonic acid or thiocarbonic acid derivative or isocyanate, protected, if appropriate, on functional groups, any protective groups present in the reaction product thus obtained are split off selectively or completely, and, in a second process step, the intermediate product thus obtained, which is free, that is to say unprotected, on at least one hydroxyl group, is reacted with an activated sulphonic acid derivative which is protected, if appropriate, on functional groups. After any protective groups present have been split off, the compounds of the formula I according to the invention are obtained
- the unblocked sugar of the formula II is reacted with 1 to 10 equivalents of the amine R 7 --NH 2 in question in a first process step in a manner which is known per se in a suitable solvent or without a solvent, if appropriate in the presence of a catalyst, at temperatures between 0° C. and 80° C. and, after working up, the glycosylamines in question are usually obtained in high yields as amorphous or crystalline solids or as viscous syrups.
- the glycosylamine is then reacted with 1 to 10 equivalents of an acyl derivative of the formula R 1 --Y--CO--X", in which R 1 and Y have the abovementioned meaning and X" designates halogen or a leaving group which is customary in acylation reactions, preferably an activating ester radical, or a group O--OC--Y--R 1 , with the above meaning for Y and R 1 , or 1 to 10 equivalents of an isocyanate of the formula R 1 --NCO, the reaction being carried out in an organic or aqueous-organic solvent at temperatures between -30° C. and 80° C., if appropriate in the presence of a base, and, when the reaction has ended, the reaction product is worked up in the customary manner.
- R 1 and Y have the abovementioned meaning
- X designates halogen or a leaving group which is customary in acylation reactions, preferably an activating ester radical, or a group O--OC-
- X"' represents halogen
- reaction being carried out in an organic or aqueous-organic solvent at temperatures between -30° C. and 80° C., if appropriate in the presence of a base, and, when the reaction has ended, the reaction product is worked up in the customary manner.
- the first process step in the preparation of the compounds of the formula I according to the invention is thus the reaction of a sugar with an amine of the type R 7 --NH 2 on the aromeric carbon atom, water being split off, to give the glycosylamine in question.
- Amines R 7 --NH 2 which are liquid at room temperature can be reacted directly with the sugar, that is to say without a solvent. This reaction is carried out at temperatures between 0° C. and 100° C., preferably at 25° C. to 70° C.
- Suitable catalysts are mineral acids, such as, for example, hydrochloric acid, sulphuric acid or nitric acid, or short-chain carboxylic acids, such as acetic acid or propionic acid, which can be employed in amounts of 0.001 to 0.03 equivalent.
- amines R 7 --NH 2 which are solid at room temperature also preferable, to carry out the preparation of the glycosylamines in the presence of a solvent.
- the reaction is then preferably carried out in the presence of a diluent which is inert under the reaction conditions and which is preferably such that at least either the reactants or the reaction products dissolve in it.
- a diluent which is inert under the reaction conditions and which is preferably such that at least either the reactants or the reaction products dissolve in it.
- Possible diluents are alcohols, such as methanol, ethanol, propan-1-ol and propan-2-ol, ethers, such as tetrahydrofuran and dioxane, and also dimethylformamide, the addition of water being preferred-except when alcohols are used.
- water by itself is also preferably suitable as the solvent. It may also be advantageous to use the alkanols as a mixture with water.
- reaction temperatures when solvents are used in the preparation of the glycosylamines are between -10° C. and 120° C., preferably between 30° C. and 70° C.
- the diluent in question can be added, as desired, before or during the reaction.
- addition before the reaction is preferable.
- glycosylamines prepared as described above crystallize out either directly or after cooling, and can be precipitated or made to crystallize by addition of suitable auxiliary solvents, preferably of low polarity, such as acetone, diethyl ether, cyclohexane, ethyl acetate or petroleum ether, if appropriate with cooling, and any excess amine R 7 --NH 2 present can be removed by washing or recrystallizing the product in a manner which is known per se.
- suitable auxiliary solvents preferably of low polarity, such as acetone, diethyl ether, cyclohexane, ethyl acetate or petroleum ether, if appropriate with cooling, and any excess amine R 7 --NH 2 present can be removed by washing or recrystallizing the product in a manner which is known per se.
- the second process step in the preparation of the compounds of the formula I according to the invention is selective N-acylation of a glycosylamine obtained as described above with an acyl derivative of the formula R 1 --Y--CO--X" with the abovementioned meaning of R 1 , Y and X", or an isocyanate of the formula R 1 --NCO.
- the third process step in the preparation of the compounds of the formula I according to the invention is selective O-sulphonylation of a protected or unprotected N-acylated aminoglycoside described above with a sulphonyl derivative of the formula ##STR29## with the abovementioned meaning of R 6 and X"'.
- Preferred carboxyl derivatives R 1 --Y--CO--X" which are known per se are anhydrides, activated esters and acid halides, preferably chlorides, and preferred sulphonyl derivatives R 6 --SO 2 --X"' which are known per se are acid halides, preferably chlorides.
- These compounds are preferably reacted with the glycosyl-amines or -amides in the presence of a diluent in which the reactants are completely or only partly dissolved.
- Possible diluents are organic or inorganic solvents, preferably those which as far as possible reduce or prevent side reactions under the reaction conditions.
- the reaction can be carried out either in organic solvents, such as ethers, for example tetrahydrofuran and dioxane, or alcohols, for example ethanol and propanol, or ketones, for example acetone or methyl ethyl ketone, or in dimethylformamide, ethyl acetate or pyridine, or in mixtures of these solvents with one another and/or with water.
- organic solvents such as ethers, for example tetrahydrofuran and dioxane, or alcohols, for example ethanol and propanol, or ketones, for example acetone or methyl ethyl ketone, or in dimethylformamide, ethyl acetate or pyridine, or in mixtures of these solvents with one another and/or with water.
- ethers for example tetra
- R 1 --Y--COX"/R 6 SO 2 --X"' or R 1 --NCO are employed in amounts of 1 to 10 equivalents based on the glycosylamine/glycosylamide.
- the reactions can preferably be carried out in the presence of basic auxiliaries.
- basic auxiliaries All the basic compounds customary in organic synthesis, such as, for example, tertiary aliphatic or aromatic amines or alkali metal and alkaline earth metal hydroxides or carbonates, such as sodium hydroxide solution, sodium carbonate or calcium carbonate, can be used.
- the reactions are carried out at temperatures between about -30° C. and +80° C., preferably between -10° C. and +20° C.
- Suitable protective groups for sugar derivatives are described in the relevant literature (for example C. B. Reese, in Protecting Groups in Org. Chem., 1973, pages 95-143; Plenum Press). All the protective groups used in sugar chemistry and combinations thereof can be employed.
- Suitable protective groups are esters, such as acetyl, benzoyl, pivaloyl and p-methoxybenzoyl, ethers, such as benzyl, p-methoxybenzyl, allyl and 1-propenyl, alkylidene compounds, such as ethylidene, isopropylidene and benzylidene, ortho-esters, such as 1-methoxy-ethylidene and 1-ethoxy-ethylidene, silyl ethers, such as trimethylsilyl and t-butyldimethylsilyl, and organometallic compounds, such as boric acid esters or tin ethers or tin ketals, such as tributyl-stannyl or dibutyl-stannylidene.
- esters such as acetyl, benzoyl, pivaloyl and p-methoxybenzoyl
- ethers such as
- O-sulphonylated amides, ureas, carbamates and thiocarbamates obtained in this manner are isolated by processes which are known per se in the form of crystalline or amorphous solids or as viscous syrups and, if necessary, purified by recrystallization, chromatography, extraction and the like.
- the protective groups can be split off in a manner which is known per se.
- glucose (a) is reacted with octadecylamine (b) to give N-octadecyl- ⁇ -D-glucopyranosylamine (c) which is acylated in the second process step with oleoyl chloride to give N-octadecyl-N-oleoyl ⁇ -D-glycopyranosylamine (d).
- O-sulphonylation is then carried out in position 6 with methanesulphonyl chloride and N-octadecyl-N-oleoyl-(6-O-methylsulphonyl- ⁇ -D-glycopyranosyl)-amine (I) is obtained.
- the invention also relates to salts of the compounds of the formula I.
- these are, above all, the nontoxic salts which are customarily pharmaceutically usable, for example alkali metal or ammonium salts, or hydrochlorides, hydroacetates or chlorides or acetates.
- the compounds of the invention exhibit a pronounced defense-increasing action. It has been found that the class of compound increases antibody synthesis by the immune system in an antigen-specific manner and moreover intensifies the non-specific defense intrinsic to the host. These results have been obtained with the aid of the following experimental design.
- SE sheep erythrocytes
- Antigen-sensitization of murine lymphocytes in the primary culture results in synthesis and release of antibodies.
- the specific antibodies discharged bind to the SE-antigen and lyse these cells by the presence of the complement (plaque formation).
- Substances of the present class of compound are capable of increasing the number of antibody-forming cells dosedependently in the range of 3-100 ⁇ g/ml (Table 1).
- NMRI mice were immunized subcutaneously (s.c.) with a suboptimum antigen dose (1 ⁇ g/animal, day 0). On suboptimum antigen stimulation, only a small number of lymphocytes in the animals were stimulated to antibody synthesis. Additional treatment of the animals with compounds of the examples mentioned from the present invention is capable of significantly increasing the antibody titre in the serum of the animals with a single administration of 10-30 mg/kg subcutaneously. The antibody titre is determined by indirect haemagglutination on day 10. The effect of the treatment is expressed by the geometric mean value of the log 2 titre.
- the immunostimulating effect of the compounds mentioned is antigen-dependent, that is to say, surprisingly, the substances cause the induction of antibody synthesis only in connection with an antigenic stimulation (in this case SE or ovalbumin). In contrast to the conventional immunostimulants mentioned, they have no mutagenic properties.
- the compounds according to the invention have the ability on the one hand to increase the immunogenicity of an antigen when mixed with this antigen, and on the other hand to increase the immunological reactivity of the organism treated on systemic administration.
- the substances mentioned are thereby capable of activating the lymphocytes responsible for antibody formation.
- the new compounds can thus be used as adjuvants, mixed with vaccines, for improving the success of the vaccine and increasing the protection from infection, imparted by immunity, by bacterial, viral or parasitic pathogens.
- the compounds described are furthermore suitable, mixed with the most diverse antigens, as adjuvants in the experimental and industrial preparation of antisera for therapy and diagnostics.
- the new compounds can moreover also be used without simultaneous supply of antigens to promote defense reactions which already proceed subliminally in humans and animals.
- the compounds are accordingly particularly suitable for stimulation of the endogenous defense, for example in cases of chronic and acute infection or selective (antigen-specific) immunological defects, and in cases of congenital and also acquired general (that is to say not antigen-specific) immunological defect conditions, such as occur in old age, in the course of severe primary diseases and, above all, after therapy with ionizing radiation or with substances having an immunosuppressant action.
- the substances mentioned can thus preferably also be administered in combination with anti-infectious antibiotics, chemotherapeutics or other healing methods, in order to counteract immunological damage.
- the substances described are also suitable for general prophylaxis of infectious diseases in humans and other animals.
- the compounds according to the invention increase the survival rate of acute bacterial infection in animal models.
- antibiotics for example penicillins, cephalosporins, aminoglycosides and the like
- chemotherapeutics for example penicillins, cephalosporins, aminoglycosides and the like
- mice which have been infected with the pathogenic strain Klebsiella 63 survived this infection after treatment (for example 18 hours before infection) with 10-40 mg/kg of the compound according to the invention in Example 7, 8 and 11, while only 0 to 30% of the untreated control animals survived.
- mice were infected with the strain Pseudomonas W. This infection leads to death within 24 hours in most control animals.
- Another group was treated with 4 mg/kg of sisomycin 30 hours after infection. It was possible to show that it was possible decisively to improve the therapeutic efficacy of the sisomycin in the experimental group which had been treated with the compounds according to the invention (for the examples, see above) 18 hours before infection.
- the pharmaceutical products of the present invention are preferably tablets or gelatin capsules, which contain the active compounds together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol and cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- diluents for example lactose, dextrose, sucrose, mannitol, sorbitol and cellulose
- lubricants for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Tablets also contain binders, for example magnesium aluminum silicate, starches, such as corn starch, wheat starch, rice starch or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrating agents, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colorants, flavor substances and sweeteners.
- Injectable products are preferably isotonic aqueous solutions or suspensions. Suppositories, ointments or creams are above all fat emulsions or suspensions.
- the pharmaceutical products can be sterilised and/or can contain auxiliaries, for example preservatives, stabilizers, wetting agents and/or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and/or buffers.
- auxiliaries for example preservatives, stabilizers, wetting agents and/or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and/or buffers.
- the present pharmaceutical products which, if desired, can contain other pharmacologically useful substances, are prepared in a manner which is known per se, for example by means of conventional mixing, granulating or coating processes, and contain from about 0.1% to about 75%, in particular from about 1% to 50%, of the active substances mentioned.
- the orally administered products of the present invention can also be provided with a coating which is resistant towards gastric juice.
- the compounds according to the invention can be used as defence-increasing and immunopotentiating agents for the treatment of chronic and acute infections (for example bacterial, viral and parasitic) and malignant tumours. They can also be used as adjuvants in vaccination, in stimulation of phagocytosis and in dysregulation of the defence and immune system.
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Abstract
Novel compounds of the formula ##STR1## in which X is hydrogen or --CH2 --OR5,
Z represents OR4, NH2 or ##STR2## R2, R3, R4 and R5 each independently is hydrogen or ##STR3## at least one of R2, R3, R4 and R5 being ##STR4## Y and W each independently is oxygen, sulphur, NH or CH2, and R1, R6, R7 and R8 each independently is an optionally substituted hydrocarbon radical with up to 50 C atoms,
stimulate the immune system.
Description
The invention relates to compounds of the general formula I ##STR5## in which X represents hydrogen or the radical --CH2 OR5,
Z represents OR4 or NHV,
wherein
V denotes hydrogen or ##STR6## Y and W are identical or different and represent oxygen, sulphur, N--H or CH2,
R2, R3, R4 and R5 are identical or different and represent hydrogen or the radical ##STR7## with the proviso that at least one of the radicals R2, R3, R4 and R5 denotes ##STR8## and R1, R6, R7 and R8 are identical or different and represent an optionally substituted hydrocarbon radical with up to 50 carbon atoms,
processes for their preparation and their use as medicaments.
A carbon radical in the meaning of radicals R1, R6, R7 and R8 is undestood, according to the invention, as meaning a straight-chain or branched alkyl radical, a straight-chain or branched, mono- or polysubstituted unsaturated alkenyl radical, a saturated or unsaturated alicyclic radical or an aromatic radical (aryl). These meanings may also occur together within the same radical R1, R6, R7 and R8, that is to say, for example, as alkylcycloalkyl, arylalkyl, alkylaryl, alkenylcycloalkyl and the like.
In the hydrocarbon radicals R1, R6, R7 and R8, individual, in general up to 5, preferably 1, 2 or 3, methylene or methine groups can also be replaced by O, S and/or N. If the chain is interrupted by N, this nitrogen carries either H or a C1 -C20 --alkyl radical or a --CO--alkyl radical, this alkyl group containing 1-20 C atoms.
R6 preferably represents an alkyl radical with 1 to 21 C atoms, preferably with 1-4 C atoms, or represents an optionally substituted aryl radical with up to 21 C atoms, preferably with up to 7 C atoms.
Examples of saturated radicals which may be mentioned here are methyl, ethyl, propyl, i-propyl, butyl and i-butyl. Examples of aryl are halogen-substituted, preferably chlorine- or bromine-substituted, or nitro-, cyano-, amido--C1 -C4 --alkyl- or C1 -C4 --alkoxy-substituted phenyl, naphthyl or biphenyl.
Preferably R1, R7 and R8 represent, as desired, alkyl or alkenyl radicals with 1 to 21 carbon atoms, preferably with 9 to 21 C atoms. Examples of saturated radicals which may be mentioned here are methyl, ethyl, propyl, i-propyl, butyl, i-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, docosyl, ethylpentyl, methyldecyl, i-propyldecyl, methyltridecyl, eicosyl, tetracosyl, triacontyl, pentahexadecyl, 1-dodecylhexadecyl, 2-dodecylhexadecyl, 3-dodecylhexadecyl, 1-hexadecyloctadecyl, 2-hexadecyloctadecyl, 3-hexadecyloctadecyl, 4-hexadecyloctadecyl, 1-octadecyleicosyl and 2-octadecyleicosyl.
Unsaturated radicals are, for example, vinyl, 1-propenyl, 2-propenyl, i-butenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-decenyl, 5-decenyl, 9-decenyl, 8-heptadecenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-pentadienyl, 8,11-heptadecanedienyl and 8,11,14-heptadecanetrienyl. In general, the longer-chain unsaturated radicals are preferred, especially the mono- or diunsaturated alkenyls with 9-21 C atoms.
The unsaturated hydrocarbon radicals can thereby be present as pure cis- or trans-isomers or as isomer mixtures.
Examples of cycloalkyl which may be mentioned are cyclopentyl, cyclohexyl, decahydronaphthyl and adamantyl.
Examples of alkyl-cycloalkyl and cycloalkyl-alkyl radicals are methylcyclopentyl, ethylcyclopentyl, n-propylcyclopentyl, i-propylcyclopentyl, butylcyclopentyl, octylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, propylcyclohexyl, butylcyclohexyl, hexylcyclohexyl, decylcyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclopentylhexyl, cyclopentyloctyl, cyclopentyldecyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylhexyl, cyclohexyldecyl, cyclopentylcyclohexylethyl, cyclohexylcyclopentylethyl and cyclohexylcyclohexylethyl.
Examples of aryl which may be mentioned are phenyl, tosyl, naphthyl and diphenyl.
Examples of aralkyl for R1, R7 and R8 are aryl-lower alkyl, such as benzyl, phenethyl or phenylhexyl.
The radicals R1, R6, R7 and R8 can be substituted, in general 1-5 times, preferably 1-3 times. Preferred possible substituents are the following: halogen, preferably F, Cl or Br, amino, C1 -C6 --alkylamino, di--C1 -C6 --alkylamino, oxo, OH, C1 -C6 --alkoxy, SH, C1 -C6 --alkylthio, C1 -C6 --alkyl--COO and C1 -C6 --alkyl--CO--NH.
Examples of cases in which the hydrocarbon radicals R1, R7 and R8 are interrupted by O, S and N or corresponding atom groupings, or are substituted, for examples, by groups containing these atoms or by halogen atoms, are methoxyethyl, ethoxyethyl, n-propoxyethyl, n-butoxyethyl, i-propoxyethyl, i-butoxyethyl, sec.-butoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, propoxyethoxyethyl, i-propoxyethoxyethyl, n-butoxyethoxyethyl, i-butoxyethoxyethyl, sec.-butoxyethoxyethyl, methoxyethoxyethoxyethyl, ethoxyethoxyethoxyethyl, n-propoxyethoxyethoxyethyl, i-propoxyethoxyethoxyethyl, n-butoxyethoxyethoxyethyl, i-butoxyethoxyethoxyethyl and sec.-butoxyethoxyethoxyethyl, if Y and/or Z represent oxygen, sulphur, N-H or CH2 ; methoxyethoxy, ethoxyethoxy, n-propoxyethoxy, i-propoxyethoxy, n-butoxyethoxy, i-butoxyethoxy, sec.-butoxyethoxy, methoxyethoxyethoxy, ethoxyethoxyethoxy, n-propoxyethoxyethoxy, i-propoxyethoxyethoxy, n-butoxyethoxyethoxy, i-butoxyethoxyethoxy and sec.-butoxyethoxyethoxy, if Y and/or Z represent CH2 ; and hydroxyheptadecenyl, oxobutyl or the amino-decyl, N-methylaminodecyl, fluoromethyl, β-hydroxytridecyl or mercaptoethyl radical.
The compounds of the formula I contain several chiral C atoms and are present as optical pure diastereomers or as diastereomer mixtures.
The compounds of the formula I according to the invention are thus carboxylic acid amides or N-alkylated or N-aralkylated carboxylic acid amides or carbamic acid, thiocarbamic acid or urea derivatives which additionally carry on the nitrogen atom substituted by the abovementioned radical R7 a single monosaccharide radical which is N-glycosidically bonded, that is to say via the anomeric carbon atom, one or more hydroxyl groups in the saccharide radical being provided with a sulphonyl radical.
Particularly preferred compounds are those in which only one of the radicals R2, R3, R4 or R5 denotes SO2 -R6, with the proviso that the other radicals R2, R3, R4 and/or R5 represent hydrogen and R6 and Z have the abovementioned meaning.
Especially preferred compounds are those in which R2, R3 and R4 represent hydrogen and R5 represents the radical SO2 --R6, Z and R6 having the abovementioned meaning.
Examples which may be mentioned are:
__________________________________________________________________________
##STR9##
Y Z R.sup.1 R.sup.6 R.sup.7
__________________________________________________________________________
CH.sub.2
OH (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR10## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR11## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.11 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR12## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " " CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR13## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.13 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR14## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " " CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR15## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
OH (CH.sub.2).sub.15 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR16## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " " CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " "
##STR17## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
NH.sub.2 (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR18## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub. 3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" NHCOCH.sub.3
(CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR19## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub. 11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR20## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" NH.sub.2 (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub. 2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR21## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2 ).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
NHCO(CH.sub.2).sub.10 CH.sub.3
(CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR22## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2 ).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub. 9 CH.sub.3
##STR23## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub. 11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
CH.sub.2
NHCONHCH.sub.3
(CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR24## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " "
##STR25## (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub. 15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
O " (CH.sub.2).sub.9 CH.sub.3
CH.sub.3 (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.9 CH.sub.3
##STR26## (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.11 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.13 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub.13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
" " (CH.sub.2).sub.15 CH.sub.3
" (CH.sub.2).sub.11 CH.sub.3
" " " " (CH.sub.2).sub. 13 CH.sub.3
" " " " (CH.sub.2).sub.15 CH.sub.3
" " " " (CH.sub.2).sub.17 CH.sub.3
__________________________________________________________________________
The invention also relates to processes for the preparation of the compounds of the formula I.
In these, compounds of the formula II ##STR27## in which X' represents hydrogen or --CH2 OH and
Z' represents OH or NHCO--W--R8,
wherein
R8 and W have the abovementioned meaning, are first reacted, either in the free, that is to say unprotected, form or in the form of protected, optionally activated derivatives, with an amino compound R7 --NH2, either in the free form or in the form of a suitable acid addition salt with the meaning of R7 described above, and the glycosylamine thereby obtained is then acylated with an activated--as is customary in acylation reactions--carboxylic acid, carbonic acid or thiocarbonic acid derivative or isocyanate, protected, if appropriate, on functional groups, any protective groups present in the reaction product thus obtained are split off selectively or completely, and, in a second process step, the intermediate product thus obtained, which is free, that is to say unprotected, on at least one hydroxyl group, is reacted with an activated sulphonic acid derivative which is protected, if appropriate, on functional groups. After any protective groups present have been split off, the compounds of the formula I according to the invention are obtained in this manner and, if necessary, can be purified by chromatography, recrystallisation, extraction or the like.
In a preferred embodiment of the process according to the invention, the unblocked sugar of the formula II is reacted with 1 to 10 equivalents of the amine R7 --NH2 in question in a first process step in a manner which is known per se in a suitable solvent or without a solvent, if appropriate in the presence of a catalyst, at temperatures between 0° C. and 80° C. and, after working up, the glycosylamines in question are usually obtained in high yields as amorphous or crystalline solids or as viscous syrups.
In the second process step, the glycosylamine is then reacted with 1 to 10 equivalents of an acyl derivative of the formula R1 --Y--CO--X", in which R1 and Y have the abovementioned meaning and X" designates halogen or a leaving group which is customary in acylation reactions, preferably an activating ester radical, or a group O--OC--Y--R1, with the above meaning for Y and R1, or 1 to 10 equivalents of an isocyanate of the formula R1 --NCO, the reaction being carried out in an organic or aqueous-organic solvent at temperatures between -30° C. and 80° C., if appropriate in the presence of a base, and, when the reaction has ended, the reaction product is worked up in the customary manner.
In a third reaction step, the derivative thus obtained, which has been reacted on the nitrogen, is then reacted, in protected or unprotected form, with 1 to 10 equivalents of a sulphonyl derivative of the formula ##STR28## in which R6 has the abovementioned meaning and
X"' represents halogen,
the reaction being carried out in an organic or aqueous-organic solvent at temperatures between -30° C. and 80° C., if appropriate in the presence of a base, and, when the reaction has ended, the reaction product is worked up in the customary manner.
The first process step in the preparation of the compounds of the formula I according to the invention is thus the reaction of a sugar with an amine of the type R7 --NH2 on the aromeric carbon atom, water being split off, to give the glycosylamine in question.
Amines R7 --NH2 which are liquid at room temperature can be reacted directly with the sugar, that is to say without a solvent. This reaction is carried out at temperatures between 0° C. and 100° C., preferably at 25° C. to 70° C. Suitable catalysts are mineral acids, such as, for example, hydrochloric acid, sulphuric acid or nitric acid, or short-chain carboxylic acids, such as acetic acid or propionic acid, which can be employed in amounts of 0.001 to 0.03 equivalent.
If is in all cases possible, and with amines R7 --NH2 which are solid at room temperature also preferable, to carry out the preparation of the glycosylamines in the presence of a solvent. The reaction is then preferably carried out in the presence of a diluent which is inert under the reaction conditions and which is preferably such that at least either the reactants or the reaction products dissolve in it. Possible diluents are alcohols, such as methanol, ethanol, propan-1-ol and propan-2-ol, ethers, such as tetrahydrofuran and dioxane, and also dimethylformamide, the addition of water being preferred-except when alcohols are used. Moreover, in the case of short-chain amines R7 --NH2, water by itself is also preferably suitable as the solvent. It may also be advantageous to use the alkanols as a mixture with water.
The reaction temperatures when solvents are used in the preparation of the glycosylamines are between -10° C. and 120° C., preferably between 30° C. and 70° C.
The diluent in question can be added, as desired, before or during the reaction. In the case of long-chain amines R7 --NH2, addition before the reaction is preferable.
The glycosylamines prepared as described above crystallize out either directly or after cooling, and can be precipitated or made to crystallize by addition of suitable auxiliary solvents, preferably of low polarity, such as acetone, diethyl ether, cyclohexane, ethyl acetate or petroleum ether, if appropriate with cooling, and any excess amine R7 --NH2 present can be removed by washing or recrystallizing the product in a manner which is known per se.
The second process step in the preparation of the compounds of the formula I according to the invention is selective N-acylation of a glycosylamine obtained as described above with an acyl derivative of the formula R1 --Y--CO--X" with the abovementioned meaning of R1, Y and X", or an isocyanate of the formula R1 --NCO.
The third process step in the preparation of the compounds of the formula I according to the invention is selective O-sulphonylation of a protected or unprotected N-acylated aminoglycoside described above with a sulphonyl derivative of the formula ##STR29## with the abovementioned meaning of R6 and X"'.
Preferred carboxyl derivatives R1 --Y--CO--X" which are known per se are anhydrides, activated esters and acid halides, preferably chlorides, and preferred sulphonyl derivatives R6 --SO2 --X"' which are known per se are acid halides, preferably chlorides.
These compounds are preferably reacted with the glycosyl-amines or -amides in the presence of a diluent in which the reactants are completely or only partly dissolved.
Possible diluents are organic or inorganic solvents, preferably those which as far as possible reduce or prevent side reactions under the reaction conditions. The reaction can be carried out either in organic solvents, such as ethers, for example tetrahydrofuran and dioxane, or alcohols, for example ethanol and propanol, or ketones, for example acetone or methyl ethyl ketone, or in dimethylformamide, ethyl acetate or pyridine, or in mixtures of these solvents with one another and/or with water. The use of anhydrous solvents is generally preferable.
The compounds R1 --Y--COX"/R6 SO2 --X"' or R1 --NCO are employed in amounts of 1 to 10 equivalents based on the glycosylamine/glycosylamide.
If acid halides and anhydrides are used, the reactions can preferably be carried out in the presence of basic auxiliaries. All the basic compounds customary in organic synthesis, such as, for example, tertiary aliphatic or aromatic amines or alkali metal and alkaline earth metal hydroxides or carbonates, such as sodium hydroxide solution, sodium carbonate or calcium carbonate, can be used.
The reactions are carried out at temperatures between about -30° C. and +80° C., preferably between -10° C. and +20° C.
In cases where selective reaction of a hydroxyl group cannot be carried out because either a less reactive secondary hydroxyl group of the sugar residue is to be reacted with the radical ##STR30## with the abovementioned meaning of R6, in the presence of a more reactive primary hydroxyl group, or a secondary hydroxyl group is to be reacted selectively with the radical ##STR31## in the presence of other secondary hydroxyl groups, or a less reactive hydroxyl group is to be reacted with the radical ##STR32## with the abovementioned meaning of R6, in the presence of a reactive amino group, the actual sulphonylation reaction is to be preceded by a number of protective group operations in which the hydroxyl group to be reacted with the radical ##STR33## is selectively present in the free state, that is to say unsubstituted, at the end of the blocking reactions. The hydroxyl groups or amino group which are not to be reacted must thus be blocked before the sulphonylation.
Suitable protective groups for sugar derivatives are described in the relevant literature (for example C. B. Reese, in Protecting Groups in Org. Chem., 1973, pages 95-143; Plenum Press). All the protective groups used in sugar chemistry and combinations thereof can be employed.
Examples of suitable protective groups are esters, such as acetyl, benzoyl, pivaloyl and p-methoxybenzoyl, ethers, such as benzyl, p-methoxybenzyl, allyl and 1-propenyl, alkylidene compounds, such as ethylidene, isopropylidene and benzylidene, ortho-esters, such as 1-methoxy-ethylidene and 1-ethoxy-ethylidene, silyl ethers, such as trimethylsilyl and t-butyldimethylsilyl, and organometallic compounds, such as boric acid esters or tin ethers or tin ketals, such as tributyl-stannyl or dibutyl-stannylidene.
The carbohydrate derivatives blocked by these protective groups are then reacted with the group ##STR34## on the still free hydroxyl group(s) in a suitable solvent. Suitable solvents and suitable processes for the sulphonylation are those mentioned above.
The O-sulphonylated amides, ureas, carbamates and thiocarbamates obtained in this manner are isolated by processes which are known per se in the form of crystalline or amorphous solids or as viscous syrups and, if necessary, purified by recrystallization, chromatography, extraction and the like.
In the case of compounds with protected hydroxyl or amino groups in the glycosyl part, the protective groups can be split off in a manner which is known per se.
The following equation is intended to illustrate by way of example one of the preferred embodiments of the preparation, according to the invention, of compounds of the formula I: ##STR35##
In the first process step, glucose (a) is reacted with octadecylamine (b) to give N-octadecyl-β-D-glucopyranosylamine (c) which is acylated in the second process step with oleoyl chloride to give N-octadecyl-N-oleoyl β-D-glycopyranosylamine (d). In the third process step, O-sulphonylation is then carried out in position 6 with methanesulphonyl chloride and N-octadecyl-N-oleoyl-(6-O-methylsulphonyl-β-D-glycopyranosyl)-amine (I) is obtained.
The invention also relates to salts of the compounds of the formula I. These are, above all, the nontoxic salts which are customarily pharmaceutically usable, for example alkali metal or ammonium salts, or hydrochlorides, hydroacetates or chlorides or acetates.
The compounds of the invention exhibit a pronounced defense-increasing action. It has been found that the class of compound increases antibody synthesis by the immune system in an antigen-specific manner and moreover intensifies the non-specific defense intrinsic to the host. These results have been obtained with the aid of the following experimental design.
Increase in the primary humoral immunity in vitro against sheep erythrocytes (SE).
It is possible experimentally to induce the development of a humoral immune response in heterologous red blood cells by primary immunisation of murine spleen cells in suspension cultures in vitro (R. I. Mishell and R. W. Dutton, J. Exp. Med. 126, 423 (1967)). For this, Balb/c murine spleen cells are cultured for 5 days in the presence of the antigen (SE) and the test substance. The cells are harvested, washed and plated out in semi-solid agar together with the antigen and complement and the agar is incubated for 2 hours at 37° C. (N. K. Jerne, A. A. Nordin and C. Henry, "Cell bound Antibodies", eds. Amos and Koprowski, Wistar Inst. Press, Philadelphia, USA, pages 109 (1963)). Antigen-sensitization of murine lymphocytes in the primary culture results in synthesis and release of antibodies. The specific antibodies discharged bind to the SE-antigen and lyse these cells by the presence of the complement (plaque formation). Substances of the present class of compound are capable of increasing the number of antibody-forming cells dosedependently in the range of 3-100 μg/ml (Table 1).
TABLE 1
______________________________________
Effect of selected O--sulphonyl-glycosylamide
analogues of the present classes of compound on
antibody synthesis in vitro.
Substance
Antibody-discharging cells/culture
as a function of the dose (μg/ml)
Example No.
0 1 3 10 30 100
______________________________________
11 1460 1840 4380 4040 12,320
n.p..sup.(1)
8 1135 3060 n.p. 2890 n.p. 3240
10 2560 2500 3020 3840 6400 9560
14 495 5380 6140 11500 11520 13880
______________________________________
.sup.(1) not performed
Increase in the primary humoral immunity in vivo against the soluble antigen ovalbumin
NMRI mice were immunized subcutaneously (s.c.) with a suboptimum antigen dose (1 μg/animal, day 0). On suboptimum antigen stimulation, only a small number of lymphocytes in the animals were stimulated to antibody synthesis. Additional treatment of the animals with compounds of the examples mentioned from the present invention is capable of significantly increasing the antibody titre in the serum of the animals with a single administration of 10-30 mg/kg subcutaneously. The antibody titre is determined by indirect haemagglutination on day 10. The effect of the treatment is expressed by the geometric mean value of the log2 titre.
TABLE 2
______________________________________
Adjuvantive effect of selected compound
according to the invention in-vivo using the
example of the soluble antigen ovalbumin.
Dose (mg/kg)
Substance
0 3 10 30
Example No.
Haemagglutination titre (Log2)
______________________________________
7 4.0 5.4.sup.(1)
5.8 6.4
8 4.2 5.4 5.6 6.2
15 4.4 5.0.sup.(2)
6.0 6.8
14 4.0 4.6.sup.(2)
6.2 6.6
______________________________________
.sup.(1) all the values are significantly increased (p < 0.01)
.sup.(2) not significant
In contrast to other, for example bacterial, immunostimulants, such as LPS from Gram-negative bacteria, the immunostimulating effect of the compounds mentioned is antigen-dependent, that is to say, surprisingly, the substances cause the induction of antibody synthesis only in connection with an antigenic stimulation (in this case SE or ovalbumin). In contrast to the conventional immunostimulants mentioned, they have no mutagenic properties.
Tolerance
Although compounds of the type described already display their potentiating action on mice, for example, after an individual dose of 10 mg/kg intraperitoneally or perorally, no toxic effects are observed even on administration of 100 mg/kg. The substances mentioned therefore have a good tolerance.
The compounds according to the invention have the ability on the one hand to increase the immunogenicity of an antigen when mixed with this antigen, and on the other hand to increase the immunological reactivity of the organism treated on systemic administration. The substances mentioned are thereby capable of activating the lymphocytes responsible for antibody formation.
The new compounds can thus be used as adjuvants, mixed with vaccines, for improving the success of the vaccine and increasing the protection from infection, imparted by immunity, by bacterial, viral or parasitic pathogens.
The compounds described are furthermore suitable, mixed with the most diverse antigens, as adjuvants in the experimental and industrial preparation of antisera for therapy and diagnostics.
The new compounds can moreover also be used without simultaneous supply of antigens to promote defense reactions which already proceed subliminally in humans and animals. The compounds are accordingly particularly suitable for stimulation of the endogenous defense, for example in cases of chronic and acute infection or selective (antigen-specific) immunological defects, and in cases of congenital and also acquired general (that is to say not antigen-specific) immunological defect conditions, such as occur in old age, in the course of severe primary diseases and, above all, after therapy with ionizing radiation or with substances having an immunosuppressant action. The substances mentioned can thus preferably also be administered in combination with anti-infectious antibiotics, chemotherapeutics or other healing methods, in order to counteract immunological damage. Finally, the substances described are also suitable for general prophylaxis of infectious diseases in humans and other animals.
The compounds according to the invention increase the survival rate of acute bacterial infection in animal models.
They can be used by themselves as a prophylactic agent, for combating existing infections or in combination with antibiotic therapy for increasing the therapeutic effect of antibiotics and chemotherapeutics (for example penicillins, cephalosporins, aminoglycosides and the like) on infected humans and animals.
Description of the experiment
It has been found that infections in mice with pathogenic germs which lead to the death of the experimental animals within 24-48 hours can be treated prophylactically--preferably intraperitoneally--with 1-80 mg/kg of the compounds according to the invention. This applies to a large number of Gram-positive (for example Staphylococci) and Gram-negative (for example E. coli, Klebsiella, Proteus and Pseudomonas) pathogens.
This list is by way of example and is in no way to be interpreted as limitative. Thus, for example, 40 to 100% of mice which have been infected with the pathogenic strain Klebsiella 63 survived this infection after treatment (for example 18 hours before infection) with 10-40 mg/kg of the compound according to the invention in Example 7, 8 and 11, while only 0 to 30% of the untreated control animals survived.
In another experimental model, it has been possible to show that the therapeutic efficacy of antibiotics can be increased by the compounds according to the invention. Thus, mice were infected with the strain Pseudomonas W. This infection leads to death within 24 hours in most control animals. Another group was treated with 4 mg/kg of sisomycin 30 hours after infection. It was possible to show that it was possible decisively to improve the therapeutic efficacy of the sisomycin in the experimental group which had been treated with the compounds according to the invention (for the examples, see above) 18 hours before infection.
The pharmaceutical products of the present invention are preferably tablets or gelatin capsules, which contain the active compounds together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol and cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, for example magnesium aluminum silicate, starches, such as corn starch, wheat starch, rice starch or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrating agents, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colorants, flavor substances and sweeteners. Injectable products are preferably isotonic aqueous solutions or suspensions. Suppositories, ointments or creams are above all fat emulsions or suspensions. The pharmaceutical products can be sterilised and/or can contain auxiliaries, for example preservatives, stabilizers, wetting agents and/or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical products, which, if desired, can contain other pharmacologically useful substances, are prepared in a manner which is known per se, for example by means of conventional mixing, granulating or coating processes, and contain from about 0.1% to about 75%, in particular from about 1% to 50%, of the active substances mentioned.
The orally administered products of the present invention can also be provided with a coating which is resistant towards gastric juice.
The compounds according to the invention can be used as defence-increasing and immunopotentiating agents for the treatment of chronic and acute infections (for example bacterial, viral and parasitic) and malignant tumours. They can also be used as adjuvants in vaccination, in stimulation of phagocytosis and in dysregulation of the defence and immune system.
20 g of octadecylamine are dissolved in 120 ml of ethanol and the solution is warmed to 70°. 11 g of anhydrous D-glucose are added. After a clear solution has formed, stirring is continued at 70° for a further 15 minutes. The mixture is cooled to 10° and left to stand for 15 minutes. The crystal sludge formed is filtered off with suction, washed twice with ethanol and dried in vacuo.
Elemental analysis: calculated: C 66.8% H 11.4% N 3.2%: found: C 67.4% H 11.8% N 3.7%.
10 g of the compound from Example 1 are suspended in 20 ml of tetrahydrofuran and, after addition of 10 g of sodium carbonate, 10 g of dodecanoyl chloride in 10 ml of tetrahydrofuran are added dropwise. When the reaction has ended (control by thin layer chromatography on silica gel 60 in toluene/isopropanol 6:1), the solid is filtered off, the filtrate is evaporated to a syrup in vacuo and the crude product is purified by column chromatography on silica gel 60 with the eluting agent toluene/isopropanol 10:1.
αD =8° (c=1.0 in dioxane)
Preparation from D-galactose and dodecylamine according to Example 1.
Elemental analysis calculated: C 62.2% H 10.7% N 4.0%: found: C 62.5% H 10.2% N 4.4%.
Preparation according to Example 2 from 10 g of the compound according to Example 3 and 16 g of stearoyl chloride.
αD =4.4° (c=1.0 in methylene chloride)
Rf value=0.23 in toluene/n-propanol 4:1
9 g of the compound from Example 1 were suspended in 160 ml of tetrahydrofuran and 40 ml of ethanol, and 9 g of sodium carbonate were added. 5 g of decyl chloroformate, dissolved in 40 ml of tetrahydrofuran, are added dropwise to this suspension in the course of 20 minutes. When the reaction has ended, the batch is filtered and the residue on the filter is rinsed with tetrahydrofuran. The filtrate is combined with the wash solutions and evaporated in vacuo. The resulting syrup is purified by chromatography (mobile phase methylene chloride/methanol, 20:1)
Rf value: 0.37 in CH2 Cl2 /CH3 OH 10:1 Elemental analysis: calculated: C 68.3% H 11.3% N 2.3%: found: C 68.4% H 11.6% N 2.4%.
9 g of the compound from Example 1 are suspended in 160 ml of tetrahydrofuran and 40 ml of ethanol. 4.3 g of dodecyl isocyanate, dissolved in 20 ml of tetrahydrofuran, are added dropwise to this suspension in the course of 20 minutes. When the reaction has ended, the mixture is evaporated in vacuo and the resulting syrup is purified by column chromatography (mobile phase methylene chloride/methanol, 15:1)
Rf value: 0.33 in CH2 Cl2 /CH3 OH 10:1
αD =7.4° (c=1.04 in dioxane)
9.2 g (0.015 mol) of N-glucopyranosyl-N-octadecyldodecanoic acid amide are dissolved with 7 g (0.064 mol) of triethylamine in 100 ml of tetrahydrofuran, and 3.4 g (0.03 mol) of methanesulfonyl chloride, dissolved in 10 ml of tetrahydrofuran, are added dropwise at an internal temperature of -20° C. The mixture is then stirred at 20° C. for 2 days, the solid is filtered off and the filtrate is concentrated to a syrup in vacuo. This crude product is then purified by column chromatography on silica gel 60 with the eluting agent toluene/isopropanol 10:1.
Yield: 4.5 g (43% of theory).
Rf value=0.345 (toluene: isopropyl alcohol=6:1)
The following compounds can be prepared analogously:
__________________________________________________________________________
##STR36##
R.sup.2, R.sup.3 = H
Rf value (toluene:
Example
Sugar R.sup.1
Y Z R.sup.7
R.sup.6 isopropyl alcohol
__________________________________________________________________________
= 6:1)*
(8) Glucose
(CH.sub.2).sub.13 CH.sub.3
O OH (CH.sub.2).sub.11 CH.sub.3
CH.sub.3 0.310
(9) Mannose
(CH.sub.2).sub.15 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.13 CH.sub.3
CH.sub.3 0.402
(10) Glucose
(CH.sub.2).sub.9 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.17 CH.sub.3
##STR37##
0.491
(11) Galactose
(CH.sub.2).sub.15 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.11 CH.sub.3
##STR38##
0.455
(12) Glucose
(CH.sub.2).sub.15 CH.sub.3
CH.sub.2
NHCOCH.sub.3
(CH.sub.2).sub.11 CH.sub.3
CH.sub.3 0.200
(13) Glucose
(CH.sub.2).sub.9 CH.sub.3
CH.sub.2
" (CH.sub.2).sub.11 CH.sub.3
CH.sub.3 0.173
(14) Galactose
(CH.sub.2).sub.15 CH.sub.3
CH.sub.2
OH (CH.sub.2).sub.11 CH.sub.3
CH.sub.3 0.345
(15) Mannose
(CH.sub.2).sub.9 CH.sub.3
CH.sub.2
OH (CH.sub.2).sub.17 CH.sub.3
CH.sub.3 0.257
(16) Mannose
(CH.sub.2).sub.9 CH.sub.3
CH.sub.2
OH (CH.sub.2).sub.13 CH.sub.3
##STR39##
(17) Glucose
(CH.sub.2).sub.15 CH.sub.3
CH.sub.2
OH (CH.sub.2).sub.13 CH.sub.3
##STR40##
__________________________________________________________________________
*Thin layer chromatography aluminum foils, Merck, silica gel 60 F 254, 0.
mm
It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
Claims (14)
1. A compound of the formula ##STR41## in which X is hydrogen or --CH2 OR5,
Z represents OR4, NH2 or ##STR42## R2, R3, R4 and R5 each independently is hydrogen or ##STR43## at least one of R2, R3, R4 and R5 being ##STR44## Y and W each independently is oxygen, sulphur, NH or CH2, and R1, R6, R7 and R8 each independently is an unsubstituted or substituted hydrocarbon radical with up to 50 carbon atoms, said substituted hydrocarbon radical containing a substituent selected from the group consisting of F, Cl, Br, amino, C1 -C6 -alkylamino, di--C1 -C6 --alkylamino oxo, OH, C1 -C6 --alkoxy, SH, C1 -C6 --alkyl--thio, C1 -C6 --alkyl--COO and C1 -C6 --alkyl--CO--NH.
2. A compound according to claim 1, in which the hydrocarbon radicals R1, R6, R7 and R8 have up to 21 carbon atoms.
3. A compound according to claim 1, in which the hydrocarbon radicals R1 and R7 have 9-21 carbon atoms, R6 has up to 7 carbon atoms and R8 has up to 21 carbon atoms.
4. A compound according to claim 1, in which
R2, R3 and R4 each is hydrogen,
X is CH2 OR5 or CH2 OSO2 R6,
Z is OR4 and
R5, R6 and W are as defined as in claim 1.
5. A compound according to claim 1, in which
R2 and R3 each is hydrogen
X is CH2 OSO2 R6, ##STR45## R6, R8 and W are as defined as in claim 1.
6. A compound according to claim 1, wherein the compound is N-octadecyl-N-dodecanoyl-(6-0-methylsulphonyl-β-D-glucopyranosyl)-amine of the formula ##STR46##
7. A compound according to claim 1, wherein the compound is N-dodecyl-N-(6-0-methylsulphonyl-β-D-gluco-pyranosyl)-tetradecylurethane of the formula ##STR47##
8. A compound according to claim 1, wherein the compound is N-octadecyl-N-dodecanoyl-(6-0-p-tolylsulphonyl-β-D-glucopyranosyl)-amine of the formula ##STR48##
9. A compound according to claim 1, wherein the compound is N-dodecyl-N-octadecanoyl-(6-0-p-tolylsulphonyl-β-D-galactopyranosyl)-amine of the formula ##STR49##
10. A compound according to claim 1, wherein the compound is N-dodecyl-N-octadecanoyl-(2-acetylamino-2-deoxy-6-0-methylsulphonyl-β-D-glucopyranosyl)-amine of the formula ##STR50##
11. An immunostimulating composition comprising an immunostimulating effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.
12. A unit dose of a composition according to claim 11 in the form of a tablet, capsule or ampule.
13. A method of stimulating the immune system of an animal which comprises administering thereto an immunostimulating effective amount of a compound according to claim 1.
14. The method according to claim 13, wherein such compound is
N-octadecyl-N-dodecanoyl-(6-0-methylsulphonyl-β-D-glucopyranosyl)-amine,
N-dodecyl-N-(6-0-methylsulphonyl-β-D-gluco-pyranosyl)-tetradecylurethane,
N-octadecyl-N-dodecanoyl-(6-0-p-tolylsulphonyl-β-D-glucopyranosyl)-amine,
N-dodecyl-N-octadecanoyl-(6-0-p-tolylsulphonyl-β-D-galactopyranosyl)-amine or
N-dodecyl-N-octadecanoyl-(2-acetylamino-2-deoxy-6-0-methylsulphonyl-β-D-glucopyranosyl)-amine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853508025 DE3508025A1 (en) | 1985-03-07 | 1985-03-07 | SUBSTITUTED O-SULFONYL-GLYCOSYLAMIDES, METHODS FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3508025 | 1985-03-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4699899A true US4699899A (en) | 1987-10-13 |
Family
ID=6264418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/832,482 Expired - Fee Related US4699899A (en) | 1985-03-07 | 1986-02-21 | Substituted O-sulphonyl-glycosylamides, processes for their preparation and their use as medicaments |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4699899A (en) |
| EP (1) | EP0193887B1 (en) |
| JP (1) | JPS61212594A (en) |
| AT (1) | ATE44961T1 (en) |
| DE (2) | DE3508025A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891425A (en) * | 1986-02-14 | 1990-01-02 | Bayer Aktiengesellschaft | N-glycosylamide derivatives, processes for their preparation and their use as medicaments |
| US5070190A (en) * | 1988-04-16 | 1991-12-03 | Bayer Aktiengesellschaft | Substituted n-glycosylamides, process for their preparation, and their use as medicaments |
| US5476924A (en) * | 1989-01-27 | 1995-12-19 | Duke University | Protecting group for acetals and methods of using the same in the activation of saccharides |
| AU674306B2 (en) * | 1992-02-10 | 1996-12-19 | Interferon Sciences Inc. | Improved alpha interferon composition and method for its production from human peripheral blood leukocytes |
| US5872111A (en) * | 1997-05-19 | 1999-02-16 | Lever Brothers Company, Division Of Conopco, Inc. | Compositions comprising glycosylamide surfactants |
| US6290971B1 (en) * | 1995-06-15 | 2001-09-18 | Aventis Pasteur Limited | Adjuvant compositions comprising a mineral salt and another immunostimulating compound |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3537075A1 (en) * | 1985-10-18 | 1987-04-23 | Bayer Ag | METHOD FOR PRODUCING CLAUSENAMIDE |
| DE3632589A1 (en) * | 1985-10-18 | 1987-04-23 | Bayer Ag | METHOD FOR PRODUCING (GAMMA) -BUTYROLACTAMES |
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| US2808404A (en) * | 1953-05-11 | 1957-10-01 | Gen Mills Inc | Sulfated fatty urea nu-glycosides |
| US4228274A (en) * | 1976-09-28 | 1980-10-14 | Merck & Co., Inc. | 1-Substituted glycopyranosides |
| EP0091645A1 (en) * | 1982-04-14 | 1983-10-19 | Bayer Ag | Derivatives of amides of carboxylic acids in which the N atom is substituted by a glycosyl radical, method for their preparation and their use to influence the immunogenic system |
| DE3403495A1 (en) * | 1983-11-23 | 1985-05-30 | Bayer Ag, 5090 Leverkusen | PHOSPHORYLATED GLYCOSYLAMIDES, UREAS, CARBAMATES AND THIOCARBAMATES, PROCESS FOR THEIR PRODUCTION AND THEIR USE |
| EP0147777A2 (en) * | 1983-12-30 | 1985-07-10 | Troponwerke GmbH & Co. KG | Derivatives of M-glycosylated amides of carboxylic acids as a product for combating diseases of the rheumatism type |
| US4574122A (en) * | 1983-12-07 | 1986-03-04 | Bayer Aktiengesellschaft | Substituted O-acylglycosylamides, pharmaceutical compositions and method of use |
-
1985
- 1985-03-07 DE DE19853508025 patent/DE3508025A1/en active Pending
-
1986
- 1986-02-21 US US06/832,482 patent/US4699899A/en not_active Expired - Fee Related
- 1986-02-28 EP EP86102609A patent/EP0193887B1/en not_active Expired
- 1986-02-28 AT AT86102609T patent/ATE44961T1/en not_active IP Right Cessation
- 1986-02-28 DE DE8686102609T patent/DE3664634D1/en not_active Expired
- 1986-03-06 JP JP61047489A patent/JPS61212594A/en active Pending
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| US2808404A (en) * | 1953-05-11 | 1957-10-01 | Gen Mills Inc | Sulfated fatty urea nu-glycosides |
| US4228274A (en) * | 1976-09-28 | 1980-10-14 | Merck & Co., Inc. | 1-Substituted glycopyranosides |
| EP0091645A1 (en) * | 1982-04-14 | 1983-10-19 | Bayer Ag | Derivatives of amides of carboxylic acids in which the N atom is substituted by a glycosyl radical, method for their preparation and their use to influence the immunogenic system |
| DE3403495A1 (en) * | 1983-11-23 | 1985-05-30 | Bayer Ag, 5090 Leverkusen | PHOSPHORYLATED GLYCOSYLAMIDES, UREAS, CARBAMATES AND THIOCARBAMATES, PROCESS FOR THEIR PRODUCTION AND THEIR USE |
| EP0143385A2 (en) * | 1983-11-23 | 1985-06-05 | Bayer Ag | Phosphorylised glycosil amides, ureas, carbamates and thiocarbamates, method for their preparation and their use |
| US4574122A (en) * | 1983-12-07 | 1986-03-04 | Bayer Aktiengesellschaft | Substituted O-acylglycosylamides, pharmaceutical compositions and method of use |
| EP0147777A2 (en) * | 1983-12-30 | 1985-07-10 | Troponwerke GmbH & Co. KG | Derivatives of M-glycosylated amides of carboxylic acids as a product for combating diseases of the rheumatism type |
Non-Patent Citations (1)
| Title |
|---|
| Carbohydrate Research, vol. 135, No. 2, Jan. 15, 1985, Elsevier Science Publishers B. V., Z. Smiatacz et al. * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891425A (en) * | 1986-02-14 | 1990-01-02 | Bayer Aktiengesellschaft | N-glycosylamide derivatives, processes for their preparation and their use as medicaments |
| US5070190A (en) * | 1988-04-16 | 1991-12-03 | Bayer Aktiengesellschaft | Substituted n-glycosylamides, process for their preparation, and their use as medicaments |
| US5476924A (en) * | 1989-01-27 | 1995-12-19 | Duke University | Protecting group for acetals and methods of using the same in the activation of saccharides |
| AU674306B2 (en) * | 1992-02-10 | 1996-12-19 | Interferon Sciences Inc. | Improved alpha interferon composition and method for its production from human peripheral blood leukocytes |
| US6290971B1 (en) * | 1995-06-15 | 2001-09-18 | Aventis Pasteur Limited | Adjuvant compositions comprising a mineral salt and another immunostimulating compound |
| US5872111A (en) * | 1997-05-19 | 1999-02-16 | Lever Brothers Company, Division Of Conopco, Inc. | Compositions comprising glycosylamide surfactants |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3508025A1 (en) | 1986-09-11 |
| EP0193887A2 (en) | 1986-09-10 |
| ATE44961T1 (en) | 1989-08-15 |
| EP0193887B1 (en) | 1989-07-26 |
| JPS61212594A (en) | 1986-09-20 |
| EP0193887A3 (en) | 1987-03-25 |
| DE3664634D1 (en) | 1989-08-31 |
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